The majority of people worldwide are persistently infected with latent viruses. These viruses can reactivate from latency at any time, leading to recurrent diseases for the life of the host. It is currently unknown how the host immune response interacts with latent virus to prevent reactivation while preventing pathology due to overactive immunity. The goal of this research proposal is to determine the contributions of viral latency and reactivation in regulating the generation and maintenance of antiviral CDS T cell immunity using a well-characterized mouse model of viral infection and latency. We hypothesize that the antiviral CDS T cell response hierarchy changes over time due to persistent stimulatory signals from latently-infected cells. To test this hypothesis, the first aim of this proposal will analyze the CDS T cell repertoire at various times after murine gamma-herpesvirus-68 infection to assess the functionality, activation status, and changes in the hierarchy of antiviral CDS T cells. By understanding the composition of the antiviral immune response, we may be able to identify specific viral epitopes with which to target therapeutic vaccination strategies. Latently-infected cells and cells undergoing viral reactivation from latency could present disparate viral antigens to circulating CDS T cells. In the second aim of this proposal, we will examine the CDS T cell hierarchy in the absence of viral latency or reactivation by utilizing infections with recombinant viruses that either cannot reactivate from or establish latency. The results of this aim will provide us essential insight into the regulation of the immune response in the face of an ongoing persistent infection, and may lead us to unique prophylactic vaccine strategies. PUBLIC HEALTH RELEVANCE: It is imperative to understand the interactions between the host immune response and latent viral pathogens if effective preventative or therapeutic vaccinations are to be developed. Results from these studies will have important implications in the design of vaccines that elicit the host CDS T cell response to prevent viral reactivations from latency.